Salicylamides and compositions thereof

ABSTRACT

3-tert.Butyl-5-nitro-N-pyrid-2&#39;&#39;-yl salicylamides which have antiparasitic activity, compositions thereof and methods of controlling parasites in animals infected therewith.

United 1191 1111 3,917,625 L et l- 1451 Nov. 4, 1975 [54] SALICYLANHDES AND COMPOSITIONS 2,899,437 8/1959 Shapiro, et a1. 260/295 AM THEREOF 3,270,026 8/1966 Bercer, et a1 260/295 AM 3,376,289 4/1968 Schmidt 260/295 AM Inventors: gs ga fi, l l g h 3,406,168 10/1968 Schmidt 260/295 AM r e w t of E a e OTHER PUBLICATIONS [73] Assignee: Smith Kline & French Laboramries Samepma, Chem1cal Abstracts 55: l0440(d).

1 Profft, Chemical Abstracts 60: 4056(f).

Limited, Welwyn Garden City, England Jensen, et a1., Chem1cal Abstracts 44: 1454(1) (1950). May, Chemical Abstracts: 43:693(b) (1949). [22] Flled' 1973 loffe et al., Chemical Abstracts 54:10938(b) (1960). [21] Appl. No.: 415,205 Schraufstaetter et a1. Chemical Abstracts 56: 466lg [30] Forelgn Applifatm'priority Data Primary Examiner-Norman A. Drezin Dec. 6, 1972 United Kmgdom 56234/72 Attorney Agent or S K Ri h D F ;W'll' H. Ed rt 52 US. Cl. 260/295 AM; 2150/2943 F; 260/294.9; ogglo lam g6 on 260/999', 424/232 51 1111131 c070 213/61 [57] F [58] Field of Search 260/295 AM; 124/232 e t -py -y sallFylamldes whlch have antlparasmc activity, composmons thereof and 5 References Cited methods of controlling parasites in animals infected 1 UNITED STATES PATENTS 1 2,554,186 5/1951 Goldberg et a1 2607295 AM 14 Claims, N0 Drawings SALICYLAMIDES AND COMPOSITIONS THEREOF The present invention relates to salicylamides and, in 5 particular, to certain substituted 3t ert.butyl-5-n itro-N- pyrid-2-yl salicylamides, to methods for their preparation and to compositions comprising these compounds. The compounds of the present invention possess activity against parasitic worms in particular against'liver flukes in ruminant animals and thus the present invention also relates to methods of controlling these parasitic worms in animals by the administration to the animals of compositions comprising the salicylamides.

Throughout the present specification, by the terms lower alkyl and lower alkoxy we mean respectively an alkyl and analkoxy group containing from 1 to 4 carbon atoms.

According to the present invention we provide compounds of the following formula I;

(more on X /'5 CO.NH--

1- M R Z FORMULA I wherein R is hydrogen, or lower alkyl, preferably methyl; and X, Y and Z, which may be the same or different, are hydrogen, halogen, lower alkyl, lower alkoxy, nitro, cyano, sulphonamido or carbalkoxy; provided that X, Y and Z are not simultaneously all hydrogen.

The preferred compounds of Formula I which have particularly useful activity against parasitic worms are those wherein R is hydrogen or methyl; X is hydrogen, methyl, or halogen; Y is nitro or halogen and Z is hydrogen. t

Specific preferred compounds are the following:

3-tert. butyl-S-nitro-6-methyl-N(4'-methyl-5'-nitropyrid-2-yl) salicylamide 3-tert. butyl-- nitro-N-( 5 '-chloropyrid-2 -yl )salicylamide 1 butyl-S-nitro-N- 5 '-nitropyrid-2 -yl )salicyla- 3-tert.

mide

3-tert. butyl-5-nitro-N-( 4 -methyl-5 -nitropyrid-2 yl)salicylamide 3-tert. butyl-5-nitro-N-(5-nitro-6i-methylpyrid-2- yl)salicylamide The compounds of the present invention may be prepared by processes which commence from a compound of the following Formula II:-

(Ha hia coon R FORMULA l1 wherein R has the same significance as in Formula I.

In one such process, the compound of Formula II is first nitrated to produce the compound of Formula III wherein R has the same significance as in Formula I and G is hydrogen. Any suitable procedure may be used for this nitration reaction, for example it may be carried out using concentrated nitric acid in glacial acetic acid whilst controlling the temperature at about l015C.

(Hzi )a FORMULA Ill FORMULA [V wherein X, Y and Z have the same significance as in Formula I. The substance of Formula III wherein G is p-nitrophenyl may be prepared from the substance of that formula wherein G is hydrogen by reaction of the latter with thionyl chloride and then with p-nitrophenol. It will be obvious that the substance of Formula III wherein G is p-nitrophenyl may be prepared from the substance of Formula II by first forming the pnitrophenyl ester of that substance and then nitrating.

In the case of certain compounds it is possible to obtain thesubstance of Formula I by reacting the substance of Formula III wherein G is hydrogen directly with the amine of Formula IV in a suitable solvent such as benzene, chlorobenzene or toluene and in the presence of a halogenating condensation agent such as phosphorous trichloride. I

65 The present invention also relates to anti-parasitic compositions comprising as the or an active ingredient an effective but non toxic quantity of a compound of Formula I together with a pharmaceutically acceptable diluent or carrier. We also provide a method of controlling parasitic worrns, in particular flukes, which comprises administering our anti-parasitic composition to a host animal such as a ruminant animal which is in need of such treatment. The composition is preferably given orally but, in certain cases, may be administered parenterally e.g. when the composition is in the form of a sterile micronised suspension or solution.

By an effective quantity of the compound of Formula 1 we mean a quantity which is active against parasites when given either for curative or prophylactic purposes to the animals concerned e.g. sheep or cattle. Our compounds are particularly active against Trematodes such as the flukes Fasciolu gigantic-(z and Fasciola hepatica. Generally-effective and non-toxic doses are found to be in the range of from 1 to 40 mg./kg., preferably from 2 to 20 mg./kg. of bodyweight. The composition, in dosage unit form, may be administered to the animals from 1 'to 5 times per day, but a single daily treatment is particularly convenient.

Veterinary compositions containing sufficient quantities of the compounds of Formula I to reach the dose levels mentioned above are prepared as known to the art by preparing tablets, capsules, boluses, liquid suspensions, powders, drenches or solutions for injection in packaged form. Alternatively, especially for prophylaxis, premix or feed compositions containing effective but non-toxic quantities of the active salicylamide are used. For these purposes particulate carriers, inert powders or, especially, feed carriers such as soybean meal, corn oil, vermiculite, diatomaceous earth, barley or wheat are used. In dosage unit or premix feed compositions the compound can comprise from about 5 to 75% of the final composition as is convenient for the farmer or veterinarian. As an example, a 5% salicylamide vermiculite or soybean meal premix can be used which will be uniformly mixed with the animal feedstuff. Alternatively, a lick or pasture block can be used for field animals.

The activity of the compounds of Formula 1 against liver flukes in sheep was estimated by means of the following procedure.

Eggs of Fasciola heptica were collected from a suitable source, e.g. the bile of donor sheep or cattle. These eggs were embryonated and snails were infected (the genus lymnea serves as intermediate host) to produce Metacercariae which are the infective forms for sheep. Each sheep in the test group was infected with 250 or more metacarcariae contained in a gelatin capsule which was administered orally and, when the infection became patent after 80 days, egg counts were carried out to determine the degree of worm burden. The test compound of Formula I was then administered and after a further 5 to 7 days a second egg count made from both treated and untreated sheep. Egg counts were repeated twice more after each of two more periods of 5 to 7 days. The livers of both treated and untreated sheep were also processed at the end of the experiment in order to recover and count F asciola hepattea.

The results of these experiments using a number of compounds of Formula 1 are set out in the following table which shows the percentage reduction of Fasc'iola lzepatica after administration of the compound in the dosage indicated. The minimum amount of compound producing only mild, transient overt symptoms of toxicity (Tolerance) is also shown in the table.

Reduction Toler- Dosuge in F. ance Compound mg/kg Hepaticu (mg/kg) 3-tert. butyl-5-nitro-6-methyl- 2 30 N-( 4'-methyl-5 'nitropyrid-Z 5 100 yl )salicylamide 3-tert. but vl-5-nitro-N-(5'- 5 100 20 chloropyrid-Z yl )salicylamide 15 100 3-tert. butyl-5-nitro-N-(5'- 2 100 2 nitropyrid-Z 'yl )salicylamide 3-tert. butyl-5-nitro-N-(4'- 15 100 20 methyl-5 -nitropyrid-2 'yl) salicylamide 3tert. butyl-5-nitro-N-(5'- I0 100 l5-20 nitro-6 'methylpyrid-Z 'yl) 15 100 salicylamide 3-tert. butyl-5-nitro-N-(5'- 2 80 iodopyrid-Z 'yl )salicylamide 5 l ()0 15-20 15 100 3-tert. butyl-5-nitro N-(5'- 2 brompyrid-Z 'yl )salicylumide 5 15-20 15 100 3-tert. but)'l-5-nitro-N-(3.S'- 5 50 l5-20 dichloropyrid-2-yl)salicylamide 15 100 3-tert. butyl-5-nitro-6-methyl- 2 100 5 N-( 5 'nitrop yrid-Z 'yl) 5 100 salicylamide 3-tert. butyl-5-nitro-6-methyl- 10 100 15-20 N-(5'nitro-6'methylpyrid-T-yl) 15 100 salicylamide 3-tert. butyl-5-nitro-6-methyl- N-( 5 'chloropyrid-Z 'yl) 15 90 20 salicylamide 3-tert. butyl-5-nitro-6-methyl- 5 50 40 salicylamide The invention is illustrated but in no way limited by the following examples:

EXAMPLE 1 Preparation of 3-tert; butyl-5 -nitro-6-methyl-N-( 4 'methyl- 5 'nitropyrid-2 yl)salicylamide i. 3-ter't. Butyl-6-methyl salicylic acid (62.4 g 0.3M) was suspended in glacial acetic acid (300 ml) and cooled to 15C. Concentrated nitricacid'(22.5 ml) was added dropwise with stirring at such a rate that the temperature was maintained at approx. 10'l5C. The mixture was stirred for 1 hour at this temp. and then poured onto crushed ice. A precipitate formed which was filtered off, washed with benzene and finally recrystallized from acetonitrile to give' 3-tert. butyl-5- nitro-6-methyl salicylic acid (30.6 g) m.p. 225-226(- dec).

ii. The 3-tert. butyl salicylic acid (23.8 g 0.094M) was refluxed in thionyl chloride ml) for 1 hour, the excess thionyl chloride removed by concentration at 15 mm and the final traces of thionyl chloride removed by reconcentration with drybenzene (80 mls). The residue was dissolved in benzene (150 mls), added to p-nitrophenol (13.5 g 0.097 mole) in benzene (150 mls) and the solution was refluxed for 4.5 hours. The benzene was removed by concentration under reduced pressure and the residual oil was crystallised from benzene/petroleum ether (1:2) and then recrystallised from water-ethanol to give p-nitrophenyl-3-tert. butyl- 5-nitro-6-methyl salicylate (15 g) m.p. l3l133C.

iii. p-Nitrophenyl-3-tert butyl-5-nitro-6-methyl salicylate (10.2 g 0.027M) and 2-amin0-4-methyl-5- nitropyridine (4.15 g, 0.027M) was heated at 180C for an hour under a nitrogen atmosphere. The reaction mixture was then stirred with 50 ml anhydrous die- 5- thylether, filtered and theproduct was crystallised from ethanol-water to give 3.-tert butyl-5rnitro-6methyl-N- (4-methyl-5j-nitropyrid-Z'-yl)salicylamide (6.1 -'g), m.p. 207-208C (.dec.). [Found: C, 55.6;-H, 5.2; N, 14.4% C ,,H- -,N',O,; zrequires: C, 55.7; -H,. 5.2; .N, 14.4%]. w

EXAMPLE 2 Preparation of 3-tert.

butyl-5-nitro-6-methyl-N-( 5 -nitropyrid-2 -yl )salicyla- 3-tert. Butyl-5-nitro-6 methy1 salicylic acid (3.4 g 0013M), 2-amino-5-nitropyridine (3.4 g 0.024M) and phosphorous trichloride (0.46 in] 0.005M) were added to 16 ml chlorobenze ne, refluxed for 3 hours and evaporated to dryness. The residuewas treated with acetone, the soluble portion evaporated, dissolved in dichloromethane, extracted with 2N hydrochloric acid and then chromatographed using a silica column. The resultant crude product was treated in turn with 10% sodium bicarbonate solution, 2N hydrochloric acid and finally water, It was then recrystallised from ethanol to 3-tert. butyl-S-nitro-6-methyl-N-( 5 '-nitropyrid-2- yl)salicyla'mide (1.1 g), m.p. 186.5189C. [Found: C, 54.6; 5.0; N, 14.7%, C -H N O requires: C, 54.5; H, 4.9; N; 1 5.0%].

EXAMPLE '3 Preparation of '3-tert. butyl-S-nitro-6-methyl-N-(5 -nitro-6-methylpyrid-2- yl)sa1icylamide p-Nitrophenyl-3-te'rt. butyl-S-nitro-6-methylsalicylate (3.74 g 0.01M) and 2-aminofS-nitro-6-methylpyridine 1.53 g 0.01M) were fused together for an hour at 180C and then allowed to cool. The resultant solid mass was chromatographed on a column of silica using dichloromethane as eluent. The crude product was recrystallised from petroleum ether (b.p. 100-120) to give 3-tert. butyl-5-nitro-6-methyl-N-(5'-nitro-6'- methylpyrid-2-yl)salicylamide (2.85 g), m.p. l64.5 165.5C. [Found: C, 55.8; H, 5.3; N, 14.4%. CigH N O6 requires: C. 55.7; H,5.2; N, 14.4%].

EXAMPLE 4 Preparation of 3-tert. butyl-S -nitro-6-methyl-N-( 5 '-chloropyrid-2 yl)salicylamide A mixture of p-nitrophenyl-3-tert. butyl-5-nitro-6- methyl salicylate (7.46 g 0.02M) and 2-amino-5- chloropyridine (2.56 g 0.02M) was fused at 180C under nitrogen for 50 minutes, The cooled product was triturated with diethyl ether to give a solid which was twice recrystallised from ethanol to give 3-tert. butyl-S- nitro-6-methyl-N-( 5 '-chloropyrid-2 -yl) salicylamide (2.0 g), m.p. 206.5207.5C. [Found: C, 56.3; H, 5.0; N, 11.5; C1, 10.0%. C H Cl N requires: C, 56.1; H, 5.0; N,.11.6; O, 9.8%].

EXAMPLE Preparation of 3-tert. butyl-5-nitro-6-methyl-N-( 3 ,5 '-dichlorpyrid-2 yl)salicylamide 3-tert. Butyl5-nitro-6-methyl "salicyliciacid (4.2 g 0.017M), 2-amino-3,5-dichloropyridine (5.45 0.03M) and phosphorous trichlo'ride (0.57 ml 0.007M) were added to chlorobenzene (20 ml), refluxed for 3 EXAMPLE 6 Preparation of 3-tert. butyl-5-nitro-N-( 5 -nitropyrid-2 '-yl )salicylamide i. 3-tert. Butyl-S-nitrosalicylic acid (5.0 g 0.021M) was refluxed for an hour with thionyl chloride (40 ml),

the excess thionyl chloride then removed by distillation and the residue twice distilled to dryness with dry benzene (20 ml) under reduced pressure. The residue was dissolved in dry benzene (20 ml) and added tota suspension of p-nitrophenol-(-3.0 g 0.022M') in dry benzene (30 ml). The mixture was refluxed for 3 hours, filtered and the filtrate concentrated to a brown oil, which crystallised. Recrystallisation from benzene/petroleum ether (b.p. 6080) and then from acetonitrile/water yielded p-nitrophenyl-3-tert. butyl-S- nitrosalicylate as pale yellow needles (2.0 g), m.p. 152C. [Foundz C, 56.6; H, 4.5; N, 7.8% C, 'H N O requires: C, 5617; H, 4.5; N, 7.8%].

ii. p-Nitrophenyl-3-tert. butyl-5-nitrosalicylate (5.0 g 0014M) and 2-amino-5-nitropyridine (1.9 g 0.014M) were dissolved in 1,2,4-trichlo robenzene and heated for an hour at C. The solvent was removed by vacuum distillation and the residue extracted with diethyl ether. Evaporation of the ethereal extract and recrystallisation of the residue twice from methanol yielded 3-tert. butyl-S-nitro-N-(S '-nitropyrid-2 -yl) salicylamide 1.55 g), m.p. 2092l0C. [-Found: C, 53.1; H, 4.5; N, 15.2%. C H N O requires: C, 53.3; H, 4.5; N, 16.5%.]

EXAMPLE 7 Preparation of 3-tert. butyl-5-nitro-N-( 4 -methyl-5 '-nitropyrid-2 '-y1) salicylamide i. 3-tert. Butyl-salicylic acid (22 g 0.11M) was refluxed with thionyl chloride (100 ml) for 20 minutes, the excess thionyl chloride was then removed and the residue was dissolved in benzene. p-Nitrophenol (15.8 g 0.1 1M) was added and the solution was refluxed for 5 hours, after which time the benzene was removed to yield a dark oil. This oil was dissolved in diethyl ether and, after extraction with. 10%sodium bicarbonate solution, the etheral solutionwasevaporated and the residue was crystallised from petroleum ether (B.pt. 60/80) to give p-nitrophenyl-3-tert. butyl-salicylate (32.9 g), m.p. 89.590.5C.

ii. p-Nitrophenyl-3-tert. butyl-salicylate (32.9 g 0.10M) was dissolved in glacial acetic acid and concentrated nitric acid (33 ml) was added dropwise, the temperature being maintained below 40C throughout the addition. The temperature was then reduced to 10C for 30 minutes, the solution poured onto crushed ice and the precipitated product filtered off. Recrystallisation from petroleum ether (b.p. 60-80) gave pure pnitrophenyl-3-tert. butyl-S-nitrosalic-ylate ('26.0-g)-m.p. l'5,0-15 1C.

iii. p-Nitrophenyls3-tert. butyI-S-nitrosalicylate (2.8 g 0008M) and 2-amino-4-methyl-S-nitropyridine (1.2 g 0008M) were heated at 180C for an hour under a nitrogen atmosphere; Ethanol (20 ml) and a few drops of water were added and vigorous stirring resulted in a crystalline product which was chromotographed on a silica column using dichloromethane as eluent. The productwas crystallised from aqueous ethanol to give 3-tert. butyl--nitrol-'N 4 -methyl"-5"-nitropyrid;2 -yl) salicylamide (1.9 g), m.p. l72--173C (dec.). [Found: C, 54.8; H, 4.8; N, l5.0 C, H ,,N O requires: C, 54.5; H, 4.9; N, 15.0%.]

EXAMPLE 8 y Preparation of 3- tertbutyl-5-nitro-N-( 5 '-nitro-6' -methylpyrid-2 .-yl) i salicylamide A mixture of p-nitrophenyl-3-tert. butyl-S-nitrosalicylate (7.26 g 0.02M) and Z-amino-5-nitro-6-methylpyridine (3.0 g 0.022M) was heated; for 40 minutes at 180C and, after cooling, was allowed to stand under diethyl ether for 1,6.hours. The-product was filtered off and recrystallised three times from dioxan/ethanol to yield 3-tert. butyl-5-nitro-N-(5-nitro-6.-methylpyrid- 2-yl) salicylamide (3.0 g), .m.p; l97l98C. [Found: C, H, N'y C17H gN4O requires: C, 54.5; H, 4;9.; N, 15.0%.]

. .EXAMPILE Preparation of 3-tert. 1 butyl-5-nitro-N(5 '-iodopyrid-2 '-yl) salicylamide 5 A mixture of "p-nit'rbphenyl-3-tert. butyl-S-nitrosalicylate (7.7 g 0.021M) and 2-amino-5-iodopyridine (4.7.

g 0.021M) was heated at 180C for 40 minutes. The product was'cooled, triturated with diethyl ether and thefiltered-dff residue recrystallised] from dioxan/ethanol thr'ee times to yield 3-te1t. bu tyl-5-nitro-N-(5- iodopyrid 2'-yl) salicylamide (3.38 g), m.p. 2l42l5C.' [Found: C, 43.3; H, 3.8; N, 9.4;1, 29.0%. C H lN O requires: C, 43.6; H, 3.7; N, 9.5; I, 28.8%.]

.. EXAMPLE 10 Preparation of 3-tert. buty1-5-nitro-N-( 5 '-bromopyrid-2 -yl) salicylamide p-Nitrophenyl-3 tert. butyl-5-nitrosalicylate (5.5 g 0015M) and 2-amino-5-bromopyridine (1.88 g 0015M) were fused at 180C for 40 minutes and then allowed to cool. The resultant solid was extracted into ether, the ethereal solution evaporated to dryness and the residue,recrystallised twice from chloroform/petroleum ether to yield 3-tert butyl-5-nitro-N-(5'- bromopyrid -2l-yl) salicylamide (2.75 g), m.p. 197I98C. [Found: C, 48.9; H, 4.2; N, 10.7; Br, 19.8%. C H BrN O requires: C, 48.8; H, 4.1; N, 10.7; Br, 20.3%.] ,1

, EXAMPLE 1.1

Preparation of 3-tert. 1 butyl- 5-nitro-N-( 5 chloropyrid-2 -y1) salicylamide p-Nitrophenyl-3-t'er t. butyl-5-nitrosalicylate (7.7 g 0.021M), 2 amin0-5-Chl0r0pyridine (2.45 g 0.021M) and 1,2,4-tri'chlorobenze1ie (10 ml) were heated for 40' minutes at 180C and the resultant solution, aftercooling, was poured into petroleum ether (b.p.- 40"-6.0) (250 ml). The crudeproduc't was dissolved in 'dichloromethane and chromatographed on a silica column,-the eluent being evaporated-to dryness and the residue twice recrystallised from dichloromethane'to yield 3- tert. buty1-5 nitro-N-( 5 -chl0ropyrid-2 '-yl) salicylamide (2.6 g), m.p. 20l.5.202.5C. [Found: C, 54.7; H, 4.8; N, 12.1%. C H ClN O requiresz C, 55.0; H, 4.6; N, 12.0%.] 7

EXAMPLE 1 2 I Preparation of 3-tert.

' butyl-5-nitro-N-( 3',5'-dichloropyrid-2-yl) salicylamide .p-Nitrophenyl-3-tert. butyl-S-nitroszili'cylate (2.2 g 0.06M) and 2-amino-3,5'-dichloropyridine (1.1 g 0.06M) were fused together for 40 minutes at 180C and then cooled to yield a solid which was stirred first with water ml) containing dilute hydrochloric acid (2 ml) and then with methanol (40ml). The crude product was filtered off, dried and recrystallised twice from ether/petroleum ether (b.p. 6080) (1:2) to yield 3-tert. butyl-'5-ni tro-N-( 3 ',5 '-dichloropyrid-2 '-yl) salicylamide (1.3 g), m.p. l78"179C.. [Found: .C, 49.8; H, 4.1; N, 10.9; c1, 18.4% 0, 11, 81,0 0, requires: C, 50.0; H, 3.9; N, 10.9; Cl, 18.5%.]

EXAMPLE 13 EXAMPLE 14 A veterinary composition was prepared in the form of a sheep drench from ,the following ingredients:

3-tert.butyl-5-nitro-6-methyl-N-( 5 'cyanopyrid- Parts by weight 3-tert. Butyl-S-nitro-6-methyl-N- (4'-methyl-5 '-nitropyrid-2'-)'l) 20 salicylamide Terra alha 75.5 Tragacanth a 3.0 Sodium lauryl sulphate 1.5

These ingredients were mixed to give a water-dispersible powder, to be used orally as necessary and practical to control infections. For example, a suitable oral dosing drench can be made from 5 g of th e powder and 5 EXAMPLE 1 A ruminant bolus may be prepared from the following ingredients:

Parts by weight 3-tert. Butyl-5-nitro-6-methyl-N- (4-methyl-5'-nitropyrid-2'-yl) 5.0 salicylamide Calcium phosphate 40.0 Maize starch 5.4 Talcum L4 Gum urabic l.5 Magnesium stearate 0.5

The salicylamide and phosphate are first mixed and screened and then granulated, using half of the starch. The resultant screened and dried granules are mixed with the remaining ingredients, blended thoroughly and compressed on a bolus press. Each bolus weighs approximately 5.4 grams.

We claim:

1. A compound of the formula:

wherein R is hydrogen or lower alkyl; and X, Y and Z,

which may be the same or different, are hydrogen,

4. The compound of claim 1 wherein R is hydrogen, X is 5-chloro and Y and Z are hydrogen, being the compound 3-tert.butyl-5-nitro-N-( 5 '-chloropyrid- 2'-yl) salicylamide.

5. The compound of claim 1 wherein R is hydrogen, X is 5'-nitro and Y and Z are hydrogen, being the compound 3-tert.butyl-5-nitro-N-(5-nitropyrid-2-yl) salicylamide.

6. The compound of claim 1 wherein R is hydrogen, X is 4'-methyl, Y is 5'-nitro and Z is hydrogen, being the compound 3-tert.butyl-5-nitro-N-( 4 -methyl-5 nitropyrid-2-yl) salicylamide.

7. The compound of claim 1 wherein R is hydrogen, X is 5-nitro, Y is 6-methyl and Z is hydrogen, being the compound 3-tert.butyl-5-nitro-N-(5'-nitro-6'- methylpyrid-2-yl) salicylamide.

8. The compound of claim 1 wherein R is hydrogen, X is 5-iodo and Y and Z are hydrogen, being the compound 3-tert.butyl-5-nitro-N-( 5 '-iodopyrid-2 '-yl) salicylamide.

9. The compound of claim 1 wherein R is hydrogen, X is 5-bromo and Y and Z are hydrogen, being the compound 3-tert.butyl-5-ni.tro-N-( 5 -bromopyrid- 2-y1) salicylamide.

10. The compound of claim 1 wherein R is hydrogen, X is 3-chloro, Y is 5'-chloro and Z is hydrogen, being the compound 3-tert.butyl-5-n.itro-N-(3,5-dichloropyrid-Z -yl) salicylamide.

11. The compound of claim 1 wherein R is methyl, X is 5-nitro and Y and Z are hydrogen, being the compound 3-tert.butyl-5-nitro-6-methyl-N-( 5 nitropyrid- 2'-yl) salicylamide.

12. The compound of claim 1 wherein R is methyl, X is 5-nitro, Y is 6-methyl and Z is hydrogen, being the compound 3-tert.butyl-5-nitro-6-methy1-N-(5 -nitro- 6-methylpyrid-2'-yl) salicylamide.

13. The compound of claim 1 wherein R is methyl, X is 5-chloro and Y and Z are hydrogen, being the compound 3-tert.butyl-5-nitro-6-methyl-N-( 5 -chloropyrid-2-yl) salicylamide.

14. The compound of claim 1 wherein R is methyl, X is 3'-chloro, Y is 5'-chloro, Y is 5-chloro and Z is hydrogen, being the compound 3-tert.butyl-5-nitro-6- methyl-N-( 3 ,5 -dichloropyrid-2 '-yl) salicylamide.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3 917 DATED fiovember 4, 1975 INVENTORG) Richard I'Iartin Lee and George Sidney Sach It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 5, line 24-, 7Q. should read give Column 6, line ifi, "16.5% should read 15.6%

Signed and Scaled this tenth Day Of February 1976 [SEAL] Arrest:

RUTH c. iuAsoN c. MARSHALL DANN Arresting Officer (ummissimu'r of Patents and Trademarks 

1. A COMPOUND OF THE FORMULA:
 2. The compound of claim 1 wherein R is hydrogen or methyl; X is hydrogen, methyl or halogen; Y is nitro or halogen and Z is hydrogen.
 3. The compound of claim 1 wherein R is methyl, X is 4''-methyl, Y is 5''-nitro and Z is hydrogen being the compound 3-tert.butyl-5-nitro-6-methyl-N-(4''-methyl-5''-nitropyrid-2''-yl) salicylamide.
 4. The compound of claim 1 wherein R is hydrogen, X is 5''-chloro and Y and Z are hydrogen, being the compound 3-tert.butyl-5-nitro-N-(5''-chloropyrid-2''-yl) salicylamide.
 5. The compound of claim 1 wherein R is hydrogen, X is 5''-nitro and Y and Z are hydrogen, being the compound 3-tert.butyl-5-nitro-N-(5''-nitropyrid-2''-yl) salicylamide.
 6. The compound of claim 1 wherein R is hydrogen, X is 4''-methyl, Y is 5''-nitro and Z is hydrogen, being the compound 3-tert.butyl-5-nitro-N-(4''-methyl-5''-nitropyrid-2''-yl) salicylamide.
 7. The compound of claim 1 wherein R is hydrogen, X is 5''-nitro, Y is 6''-methyl and Z is hydrogen, being the compound 3-tert.butyl-5-nitro-N-(5''-nitro-6''-methylpyrid-2''-yl) salicylamide.
 8. The compound of claim 1 wherein R is hydrogen, X is 5''-iodo and Y and Z are hydrogen, being the compound 3-tert.butyl-5-nitro-N-(5''-iodopyrid-2''-yl) salicylamide.
 9. The compound of claim 1 wherein R is hydrogen, X is 5''-bromo and Y and Z are hydrogen, being the compound 3-tert.butyl-5-nitro-N-(5''-bromopyrid-2''-yl) salicylamide.
 10. The compound of claim 1 wherein R is hydrogen, X is 3''-chloro, Y is 5''-chloro and Z is hydrogen, being the compound 3-tert.butyl-5-nitro-N-(3'',5''-dichloropyrid-2''-yl) salicylamide.
 11. The compound of claim 1 wherein R is methyl, X is 5''-nitro and Y and Z are hydrogen, being the compound 3-tert.butyl-5-nitro-6-methyl-N-(5''-nitropyrid-2''-yl) salicylamide.
 12. The compound of claim 1 wherein R is methyl, X is 5''-nitro, Y is 6''-methyl and Z is hydrogen, being the compound 3-tert.butyl-5-nitro-6-methyl-N-(5''-nitro-6''-methylpyrid-2''-yl) salicylamide.
 13. The compound of claim 1 wherein R is methyl, X is 5''-chloro and Y and Z are hydrogen, being the compound 3-tert.butyl-5-nitro-6-methyl-N-(5''-chloropyrid-2''-yl) salicylamide.
 14. The compound of claim 1 wherein R is methyl, X is 3''-chloro, Y is 5''-chloro, Y is 5''-chloro and Z is hydrogen, being the compound 3-tert.butyl-5-nitro-6-methyl-N-(3'',5''-dichloropyrid-2''-yl) salicylamide. 